A single molecular
anchor that allows bacteria to invade the nervous system may
hold the key to treating many types of bacterial meningitis,
a UCSD School of Medicine study has found.

By blocking the molecule’s
anchoring ability, researchers may be able to find a way to
stave off the most common serious infection of the central nervous
system and a major cause of childhood death and disability.
The researchers’ findings appear in the September 2005
issue of the Journal of Clinical Investigation.

Kelly
Doran

Kelly Doran, Ph.D,
assistant professor of pediatrics, Victor Nizet, M.D., associate
professor of pediatrics, and their colleagues have identified
a gene that produces a fat-sugar complex, which in turn anchors
a molecule called LTA (short for lipoteichoic acid), found on
the bacterial cell wall. This anchoring is a necessary first
step for bacteria to cross from the bloodstream into the central
nervous system through an anatomical obstacle called the blood-brain
barrier.

“Streptococcus,
which can cause meningitis, has to penetrate the normally impermeable
blood-brain barrier in order to enter the central nervous system
and cause disease,” said Doran. “How this happens
is not well known for bacteria. We wanted to see how bacteria
interact with blood-brain barrier cells to begin the process
of crossing over into the nervous system.”

The team began by looking
for new bacterial genes that allowed them to penetrate the barrier.
Through a process that involved generating and screening thousands
of Streptococcus mutants in a laboratory model of the
human blood-brain barrier, the researchers found that a gene
called iagA (short for invasion association gene-A) played a
central role.

By producing a fat-sugar
complex that anchors LTA, iagA establishes a link that allows
bacteria to begin making its way into the nervous system. The
researchers found that removing the iagA gene from
the Streptococcus inhibited bacterial interactions
with the blood-brain barrier, reducing mortality rates up to
90 percent in mice.

“Mice that were
infected with the normal, or wild-type, Streptococcus
bacteria containing iagA died within days showing evidence
of bacterial meningitis. In contrast, most of the mice survived
when infected with bacteria missing the single iagA
gene,” Doran said. “Blocking the anchoring of LTA
on the bacterial cell surface could become new a therapeutic
target for preventing bacterial meningitis.”

Doran and Nizet noted
that the study focused on how bacteria can begin the invasion
process, and that additional Streptococcus toxins and
the body’s own immune response also contribute to the
development of meningitis. In their ongoing efforts, the researchers
are looking at all of these factors in order to paint a complete
picture of how the bacteria invade the brain and spinal cord
to produce this potentially devastating infection.

Bacterial meningitis
must be treated quickly and aggressively with antibiotics, since
up to 25 percent of affected children may die or suffer permanent
cognitive deficits, cerebral palsy, blindness, deafness or seizures.
Therefore, an early acting treatment would help reduce the high
rates of disability and death.

“Previous studies
have found that Streptococcus bacteria from infants
with serious disease have significantly higher levels of LTA
than bacterial strains in infants without symptoms,” Nizet
said. “This underscores the importance of this anchor-LTA
interaction, as well as its potential importance as a drug target.”

The researchers’
work was supported by the Burroughs Wellcome Fund, the American
Heart Association, the Edward J. Mallinckrodt, Jr., Foundation,
the United Cerebral Palsy Research Foundation and the National
Institutes of Health.

Doran and Nizet’s
colleagues include Erin Engelson, Arya Khosravi and Heather
Maisey of UCSD; Iris Fedtke and Andreas Peschel of the University
of Tübingen, Germany, and Ozlem Equils, Kathrin Michelsen,
and Moshe Arditi of Cedars-Sinai Medical Center, Los Angeles.